Obesity is a well-characterized risk factor for development of severe acute pancreatitis (AP). However, the mechanisms by which obesity increases AP severity are currently unclear. This proposal aims at developing a novel experimental model of obesity-associated severe AP. Preliminary data indicate that daily administration of a combination of interleukin-12 and interleukin 18 - two cytokines that are increased in the circulation of AP patients - for 3 to 5 days induces mild pancreatic damage in non-obese wild type mice, but very severe AP in leptin-deficient, massively obese ob/ob mice. The goal of the present project is to perform a detailed characterization of this novel model of obesity-associated severe AP with the prospect of utilizing it in future studies to identify the mechanisms linking obesity to increased AP severity. We will evaluate the kinetics of disease and perform dose-response experiments. We will also study which mediators are involved in this model by measuring local and systemic cytokine levels and acute-phase proteins, rates of apoptosis, activation of immune cells, and metabolic parameters. Depletion and neutralization experiments will attempt to identify the cell populations and cytokines which contribute to pancreatic pathology in this model. The novel model will also be compared with the well-established model of AP induced by administration of caerulein. This exploratory project will verify whether a novel, pathologically relevant model of severe AP can be used as a suitable tool to investigate the mechanisms and possible preventive/therapeutic strategies of obesity-associated severe AP. [unreadable] [unreadable]